Chemotherapy Related Toxicity

FOLFOX chronotherapy to reduce liver toxicity

Commentator: RENÉ ADAM, MD

Comment:

FOLFOX chronotherapy is defined as delivering FOLFOX at a time, over the 24-hour circadian rhythm scale, when the risk of toxicity is reduced. Many experimental and clinical studies demonstrate that administering a drug like oxaliplatin at selected times over the 24-hour scale can prevent toxicity.

Effect of chemotherapy on hepatotoxicity

Commentator: MICHAEL CHOTI, MD

Comment:

All chemotherapy can cause toxicity, but provided the chemotherapy is delivered carefully and not for a prolonged duration, either irinotecan or oxaliplatin can be administered safely without fear of liver toxicity. Some data suggest that irinotecan-based therapies or 5-FU/leucovorin alone, particularly for a prolonged duration, cause fatty liver or steatosis. On the other hand, oxaliplatin-based therapy can sometimes result in the so-called blue liver or sinusoidal dilatation. I believe it depends on the duration of therapy.

The MD Anderson study showed that patients who received irinotecan had a lot of steatohepatitis, but we find little steatohepatitis, as opposed to steatosis. Although a lot of discussions have taken place about the hepatotoxicity of irinotecan, I feel that if it is administered carefully and not for a prolonged duration, one can use irinotecan or oxaliplatin. I don’t feel strongly about one treatment versus the other. Frankly, the response rates seem to be higher with oxaliplatin. We generally use oxaliplatin in the adjuvant setting. Therefore, in the neoadjuvant setting, oxaliplatin-based regimens seem to be more desirable, but it’s not so much because of hepatotoxicity, in my opinion.

Commentator: ALAN VENOOK, MD

Comment:

Oxaliplatin, irinotecan and certainly 5-FU are associated with hepatic toxicities. Irinotecan/FOLFIRI may cause a little more steatohepatitis. FOLFOX seems to cause a somewhat different, less common lesion in terms of hepatic toxicity. Certainly, 5-FU causes fatty liver by itself.

The general belief is that this is a cumulative toxicity. We definitely see the occasional patient who has severe idiosyncratic hepatic disease from the start. However, our rule of thumb is that if we believe the tumor is resectable and we are simply using chemotherapy to verify favorable tumor biology, we’ll use chemotherapy to keep the tumor under control or to shrink the tumor a bit, but we only administer four cycles. By doing this, the risk of morbidity at the time of surgery is greatly diminished. The literature suggests that giving a vast amount of chemotherapy exposes patients to substantial risk, and this risk may be lessened if you minimize the exposure.

In the colorectal cancer setting, FOLFOX is generally used over the near equivalent FOLFIRI. A little less hepatic toxicity may arise with FOLFOX, but as we fully intend to use four cycles preoperatively, FOLFIRI is sometimes a better choice.

If the patient experiences hepatic toxicity ahead of resection, you’re stuck because you must wait. It’s difficult to detect such toxicity before the surgeon is in the operating room. The dilemma is that you may figure it out when the surgeon is in the middle of surgery — that’s why we minimize the chemotherapy. I would say that only once or twice has my surgeon ever commented that severe toxicity was encountered after only four doses of chemotherapy.

Commentator: STEVEN CURLEY, MD

Comment:

The primary reason that we administered chemotherapy before PVE was because we were concerned about the potential for growth of metastatic disease after PVE. We know that growth factors are released, and we’ve all seen patients who have had actual progression of their disease rapidly after PVE. You have to decide the best sequence, but generally, we administer two to three months of chemotherapy first, perform PVE and proceed with the liver resection four weeks later.

The effects of chemotherapy on the liver have been well described in the recent literature. Regimens containing oxaliplatin can cause a sinusoidal injury to the liver sinusoids, the so-called blue liver, but that does not necessarily cause postoperative complications to the liver. We were cautious using the irinotecan in this patient, because it can cause a nonalcoholic steatohepatitis, and we know that patients with steatohepatitis who undergo a liver resection are at an increased risk for liver insufficiency or liver failure. Fortunately, this does not occur in all patients who receive irinotecan, and this patient tolerated it quite well and had no problems with her liver.

Managing oxaliplatin-related neuropathy

Commentator: STEVEN CURLEY, MD

Comment:

We counsel patients about all of the things that, at least putatively, seem to reduce oxaliplatin-associated neurotoxicity. These things may include calcium/magnesium, and possibility vitamin supplements, although I haven’t been totally convinced. Once a patient reaches the ninth or tenth cycle of FOLFOX, most of them begin to experience some troublesome neuropathies, if they receive full-dose oxaliplatin. The degree of inconvenience depends on the individual. Some patients are still able to work full time and have no real issues. Others, such as a secretary or someone who works on a computer or types, will find it difficult to work. Patients who require fine manual dexterity at the workplace tell me that it affects them adversely — they have a real problem with it. We ask people what kind of work they do, how much they walk and if it is difficult to walk because of the neuropathy. We also ask them if it is difficult to use their fingers for fine dexterity. If we feel they may be strongly affected, we will watch them closely and will dose-reduce when they start developing any neuropathy.

The use of oxaliplatin in patients with diabetes

Commentator: STEVEN CURLEY, MD

Comment:

We were treating this patient with a curative intent so the preference was to use an oxaliplatin-based regimen for neoadjuvant therapy, recognizing that it may confound any preexisting diabetic neuropathy. Several ongoing studies are evaluating the role of diabetes in neuropathy-related oxaliplatin. Is the neuropathy worse? Does it develop after fewer cycles? These things have been suggested, but I’ve seen no definitive proof. We are watching the ongoing studies closely because we’d love to know if we should change the dose of oxaliplatin. Should you change the number of cycles of oxaliplatin, or should we treat these patients even more aggressively by using things like calcium/magnesium and other therapies that reduce the oxaliplatin-induced neuropathy?

Allergic reactions to oxaliplatin

Commentator: STEVEN CURLEY, MD

Comment:

In examination of the data from the NCCTG-N9741 trial, seven percent of patients receiving oxaliplatin had allergic reactions that led to treatment discontinuation. It doesn’t generally occur early on — rather the median time to onset was approximately six cycles. When we see allergic reactions to this agent, we can either chose an alternative regimen or try to desensitize the patient. To accomplish the later, we use miniscule amounts of drug, diluted one to 100,000, on an inpatient basis and ramp up the infusion rate and dose over time. The process takes about eight hours, and there’s approximately a 50 percent chance that the desensitization will succeed.